There is substantial evidence that immune activation is the determining factor for disease progression and co-morbidities in HIV infection. Peripheral immune activation, which is triggered by HIV, impacts the function of T cells and monocytes. HIV-induced monocyte proteins have been investigated as markers of an activated state that is tied to neuropathogenesis in the CNS. This is supported by SIV macaque models pointing to immune responses in the periphery being linked to CNS damage. In humans, an activated peripheral monocyte phenotype correlates with lower N-acetylaspartate (NAA), which is linked to neuronal dysfunction. However, there remains considerable debate whether LPS, type 1 interferon (IFN) or other factors are the causative agents. Our research shows that monocytes from HIV-infected subjects have a type 1 IFN gene expression profile. It is our overall hypothesis that in HIV disease type 1 IFN is responsible for chronic immune activation, which is associated with disease progression including cognitive impairment. We will: 1) investigate a number of variables that could produce the IFN-induced monocyte phenotype, 2) define a new IFN- induced monocyte phenotype, CD169, 3) determine the impact of immune activation on chemotaxis and cytokine elaboration and 4) determine if monocyte activation enhances LPS tolerance. Understanding the mechanism for continued activation in chronically HIV-infected individuals is crucial for mitigating CNS damage.